The accumulation of protein aggregates and impaired mitochondrial function has emerged as a common denominator in neurodegenerative diseases. The long-term objective of this application is to elucidate the cellular machinery critical for the recognition and processing of toxic entities and its importance in the pathogenesis of neurodegenerative disease. We have discovered that the ubiquitin-binding deacetylase HDAC6 is a component of Lewy bodies and plays a critical role in the clearance of protein aggregate and impaired mitochondria. In mice, loss of HDAC6 results in accumulation of protein aggregates and neurodegeneration. We have identified HDAC6 as a critical component of quality control (QC) autophagy, which has recently emerged as the key machinery responsible for eliminating protein aggregates and damaged mitochondrial. We found that QC autophagy is functionally and molecularly distinct from the well characterized starvation-induced autophagy, suggesting a novel mechanism for the disposal of toxic entities linked to neurodegeneration. In this application, we propose to elucidate the molecular mechanism by which HDAC6 controls and connects the aggresomal pathway and QC autophagy, thereby facilitating the clearance of toxic protein aggregates. By delineating the molecular composition and regulation of QC autophagy, we wish to gain novel insight into how cells process and dispose toxic protein aggregates and the mechanistic basis for the progression of neurodegenerative disease. PUBLIC HEALTH RELEVANCE: The accumulation of toxic protein aggregates and impaired mitochondrial function has emerged as a common denominator in neurodegenerative diseases. By characterizing the mechanism and protein machinery that eliminate toxic protein aggregates and damaged mitochondria, we hope to identify new avenues for developing novel therapeutic approaches for treating neurodegenerative disease.